tbuckley/cabot-search huggingface dataset:
Abstract 480: Consensus subtypes of hepatocellular carcinoma associated with clinical outcomes, response to therapies, and multiple biomarkers
Authors: Sung Hwan Lee, Ju-Seog Lee
Journal: Cancer Research (2022)

Abstract Background &amp; aims: While many studies revealed genomic subtypes of hepatocellular carcinoma (HCC), they are not translated to the clinic yet due to lack of consensus. We aim to examine consensus of genomic subtypes and uncover their clinical significance. Methods: We integrated 15 previously established genomic signatures for HCC to uncover consensus genomic subtypes. We also developed and validated a robust predictor of consensus subtype with 100 genes (PICS100). Informatics and statistics approaches were applied to find clinical relevant association of genomic features. Patient derived xenograft (PDX) models were used for testing hypothesis from analysis of genomic data. Results: We identified 5 clinically and molecularly distinct consensus subtypes. STM (STeM) is characterized by high stem cell features, vascular invasion, and poor prognosis. CIN (Chromosomal INstability) has moderate stem cell features but high genomic instability and low immune activity. IMH (IMmune High) is characterized by high immune activity. BCM (Beta-Catenin with high Male predominance) is characterized by prominent β-catenin activation, low miRNA expression, hypomethylation, and high sensitivity to sorafenib. DLP (Differentiated and Low Proliferation) is differentiated with high HNF4A activity. We also identified potential serum biomarkers that can stratify patients into 5 subtypes. Because these subtypes are highly associated with currently available treatments, our findings may provide the foundation for rationalized biomarker-based clinical trials. Conclusions: Five HCC subtypes are highly associated with response to standard and experimental treatments and highly conserved in pre-clinical models, providing a framework for selecting the most appropriate models for preclinical studies and rationalized clinical trials of new drugs. Citation Format: Sung Hwan Lee, Ju-Seog Lee. Consensus subtypes of hepatocellular carcinoma associated with clinical outcomes, response to therapies, and multiple biomarkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 480.
Abstract 861: Nuclear translocation of Axl during early breast cancer progression
Authors: Darby R. Graham, Kelly D. Hebert, Emma E. Newton, Angelica M. Gomes, Fariba Behbod, Heather L. Machado
Journal: Cancer Research (2022)

Abstract Axl is a receptor tyrosine kinase (RTK) that is activated by its ligand Gas6 and regulates proliferation, cell survival, and clearance of apoptotic cells in both normal physiology and a number of disease states. In breast cancer, Axl is overexpressed in Her2+ and triple-negative breast cancers and is associated with resistance to RTK targeted therapies. Recent studies have shown that upon kinase inhibition, the Axl intracellular domain (ICD) can translocate to the nucleus, however, the biological significance and functions for nuclear Axl are poorly understood. Furthermore, a functional role for Axl during ductal carcinoma in situ (DCIS) progression, a requisite step for invasive breast cancer, has not been established. To address whether Axl mediates localized invasion during DCIS progression, Axl was deleted in a DCIS cell line (MCF10A-DCIS.com) using a CRISPR-Cas9 approach. Deletion of Axl shows a significant decrease in progression to invasive cancer in vivo, which is accompanied by decreased proliferation, however microinvasion is unchanged as compared to wildtype. Analysis of patient samples of pure DCIS, DCIS with microinvasion, and DCIS with invasive cancer shows a significant increase in Axl expression in patients with evidence of invasion. Interestingly, there is a significant increase in nuclear Axl in all patient samples with evidence of invasion as compared to normal breast or pure DCIS, suggesting an important role for Axl-ICD in progression to invasive cancer. Soft agar assays using normal cells (MCF10A) shows that while full length Axl (Axl-FL) is sufficient to induce colonies, Axl-ICD-transduced cells do not form colonies, suggesting that Axl-ICD alone does not have oncogenic activity. However, Axl-ICD significantly increases colonies in DCIS cells, suggesting that the ICD is important in the progression of transformed cells. Ongoing studies are aimed at identifying transcriptional targets of Axl-ICD in DCIS cells. These studies will advance our understanding of how Axl mediates breast cancer progression and will have critical implications for ongoing therapeutic strategies aimed at targeting Axl. This work is supported by NIH R01CA212518 (H.L.M.) and Susan G. Komen CCR1637765 (H.L.M.). Citation Format: Darby R. Graham, Kelly D. Hebert, Emma E. Newton, Angelica M. Gomes, Fariba Behbod, Heather L. Machado. Nuclear translocation of Axl during early breast cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 861.
Abstract 1489: MicroRNA-1 targets CXCR4/FOXM1/RRM2 axis regulating small cell lung cancer growth and metastasis
Authors: Parvez Khan, Jawed A. Siddiqui, Shailendra Kumar Maurya, Tamara Mirzapoiazova, Ranjana Kanchan, Ramakanth Chirravuri Venkata, Pranita Atri, Wemin Tang, NaveenKumar Perumal, Prakash Kshirsagar, Mahek Fatima, Md Arafat Khan, Sanjib Chaudhary, Asad Ur Rehman, Imayavaramban Lakshmanan, Sidharth Mahapatra, Prakash Kulkarni, Apar Kishor Ganti, Maneesh Jain, David Oupicky, Ravi Salgia, Surinder Kumar Batra, Mohd Wasim Nasser
Journal: Cancer Research (2022)

Abstract Small cell lung cancer (SCLC) is a high-grade neuroendocrine metastatic lung cancer subtype having a universal relapse and poor prognosis. Limited or extensive-stage SCLC patients have limited therapeutic options due to a lack of potential drug targets. In the quest for novel therapeutic molecules, we performed micro-RNA sequencing from the serum samples and also analyzed bulk RNA-sequencing data from tumors of SCLC patients. We found a consistent downregulation of miR-1 in SCLC. These results were recapitulated in SCLC cell lines and tumor tissues compared to their matched normal. To assess the therapeutic potential of miR-1, we overexpressed miR-1 in SCLC cell lines that translated into decreased cell growth and oncogenic signaling. Mechanistic studies revealed that CXCR4 is a direct target for miR-1 in SCLC. Intracardiac injection of SCLC cell lines in the mouse models showed that overexpression of miR-1 decreases the distant organ metastasis, whereas miR-1 sponging potentiates aggressiveness and metastasis. Furthermore, we identified FOXM1-RRM2 as a unique downstream target of the miR-1/CXCR4 axis involved in the growth and metastasis of SCLC. Our results showed that FOXM1 directly binds to the promoter site of RRM2 and regulates its activity. Overexpression of miR-1 decreases the expression and activity of FOXM1-RRM2 through CXCR4 that reduces cell growth and metastasis. Taken together, our results suggest that miR-1 decreases SCLC metastasis by targeting the CXCR4/FOXM1-RRM2 axis and has a high potential for the development of novel SCLC therapies. Citation Format: Parvez Khan, Jawed A. Siddiqui, Shailendra Kumar Maurya, Tamara Mirzapoiazova, Ranjana Kanchan, Ramakanth Chirravuri Venkata, Pranita Atri, Wemin Tang, NaveenKumar Perumal, Prakash Kshirsagar, Mahek Fatima, Md Arafat Khan, Sanjib Chaudhary, Asad Ur Rehman, Imayavaramban Lakshmanan, Sidharth Mahapatra, Prakash Kulkarni, Apar Kishor Ganti, Maneesh Jain, David Oupicky, Ravi Salgia, Surinder Kumar Batra, Mohd Wasim Nasser. MicroRNA-1 targets CXCR4/FOXM1/RRM2 axis regulating small cell lung cancer growth and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1489.
Abstract 3711: Modulation and inhibition of prostate cancer cells by microbial metabolites and resveratrol
Authors: James Stokes, Rajesh Singh, Manoj K. Mishra
Journal: Cancer Research (2022)

Abstract The chemotherapeutic compounds resveratrol (RES) and short-chain fatty acids (SCFAs) are potent inhibitors of cancer cell proliferation during in vitro testing. These compounds are naturally occurring and present relatively low toxicity to normal cells and tissues, making them an attractive cancer treatment alternative. SCFAs are the chemical by-products of microbial activity known as fermentation. RES is a polyphenolic compound found in select fruits and vegetables and has been known for its versatility in preventing and reversing many diseases, including several cancers. Butyric and propionic acid are considered the most potent of the SCFAs found within the intestinal lumen. The prime goal of this research is to understand if the RES and SCFA compounds use a shared biological pathway(s) to fight and inhibit cancer. We used TRAMP C1 and C3 prostate cancer cells (transgenic adenocarcinoma mouse prostate) as an experimental model. These cells were treated with the RES and SCFAs both singularly and synergistically for 24hrs. The cells were analyzed to understand the potential cell toxicity and proliferation, the modulation of apoptotic and proapoptotic proteins/genes, and any change in mitochondrial membrane potential pathways. The result demonstrated that the expression of apoptogenic proteins induces programmed cell death in a mitochondria-independent manner. Therefore, the result suggests that RES and SCFAs can facilitate many critical biological functions within the host's body, including cellular respiration, nutrient assimilation, and various immunological responses to inhibit cancer cell proliferation. Citation Format: James Stokes, Rajesh Singh, Manoj K. Mishra. Modulation and inhibition of prostate cancer cells by microbial metabolites and resveratrol [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3711.
Sentinel lymph node biopsy in Merkel cell carcinoma: Rates and predictors of compliance with the National Comprehensive Cancer Network guidelines
Authors: Daniel J. Lewis, Ramie A. Fathy, Shannon Nugent, Jeremy R. Etzkorn, Joseph F. Sobanko, Thuzar M. Shin, Cerrene N. Giordano, Stacy L. McMurray, Joanna L. Walker, Junqian Zhang, Christopher J. Miller, H. William Higgins
Journal: Journal of the American Academy of Dermatology (2022)
Abstract 5696: Effect of extracellular matrix stiffness on cancer cells radiation response
Authors: Jerome Lacombe, Melinda Muccio, Frederic Zenhausern
Journal: Cancer Research (2022)

Abstract Over the past decade, it has become clear that the mechanical cues of extracellular matrix (ECM) are a major regulator of the cancer biology. In particular, ECM stiffness has shown an important role in chemoresistance modulation. However, despite the central role of radiotherapy in cancer management, little is known about the effect of ECM stiffness on cancer cells radiation response. In this study, we used polyacrylamide collagen-coated hydrogel model to reproduce a soft (0.7 kPa) and a stiff (70 kPa) matrix. The model was validated by atomic force microscopy force spectroscopy and biological analyses through cellular morphology, proliferation and YAP/TAZ mechanotransduction pathway that all confirmed the accuracy of our model. Then, lung cancer cells seeded on both soft and stiff hydrogels were irradiated, and the level of DNA damages were compared between the two conditions. First, alkaline comet assay revealed the total amount of DNA damages were higher in cells grown on a rigid ECM at 1 h post-irradiation than cells seeded on a soft matrix. Second, γH2AX/53BP1 foci assay showed that the number of DNA double strand breaks were also higher in cells grown on a rigid environment. However, the level of DNA damage was identical at 24 h post-irradiation for both stiffness, suggesting that a more efficient DNA damage repair response could take place for cells seeded in stiff matrix. In order to explain these observations, analyses on chromatin structure and nucleus shape were then performed. Data showed that cells cultured on stiff matrix displayed a larger nucleus, less condensed chromatin, and a decreased expression level of class I HDACs genes. Moreover, it was found that the level of total reactive oxygen species (ROS) and superoxide ion was also higher in cells grown on a rigid environment 24 h post-irradiation. Altogether these data suggest that a high stiffness may increase early DNA damages after irradiation, partially by remodeling chromatin that could expose DNA to radiation-induced genotoxic agents such as ROS. Additional investigations are required to understand better the mechanisms that could explain such differences, but these preliminary data highlighted the potential role of mechanical stress in cellular radiation response and paved the way to new therapeutic target for radiotherapy management. Citation Format: Jerome Lacombe, Melinda Muccio, Frederic Zenhausern. Effect of extracellular matrix stiffness on cancer cells radiation response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5696.
Abstract 5979: Evaluating therapeutic strategies against lung cancer using multispectral optoacoustic tomography
Authors: Tianyuan Wang, Hashini Wanniarachchi, Lorena Arango, Li Zhang, Li Liu
Journal: Cancer Research (2022)

Abstract Tumor hypoxia is an important feature of the microenvironment in various types of tumors. The leaky and compressed vessels in the tumor lead to impaired blood flow and oxygen delivery and cause hypoxia. Significant tumor hypoxia exists in non-small cell lung cancer (NSCLC) and is closely associated with radiation-resistant and poor survival. Recently, we have identified a new class of antitumor drugs, cyclopamine tartrate (CycT) and heme-sequestering peptide 2 (HeSP2). They are heme-targeting agents that effectively inhibit NSCLC oxidative metabolism, oxygen consumption, and ATP generation, which lead to the suppression of tumor progression. By using multispectral optoacoustic tomography (MSOT), an advanced noninvasive imaging modality that monitors the changes in blood oxygen saturation and vascular function in real-time, we observed the effect of heme-targeting agents in normalizing tumor vasculature and alleviating tumor hypoxia. To investigate the impact of heme-targeting agent on mediating the lung cancer radiotherapy response, we characterized the vasculature and antigenic profile of NSCLC growth during the treatment of CycT in combination with radiotherapy by performing MSOT, together with other imaging approaches including bioluminescence imaging (BLI) and immunohistochemistry (IHC). We demonstrated that the heme-targeting agents increased tumor radiation sensitivity by regulating tumor vasculature and oxygenation. Our novel combination therapy can be a powerful strategy in improving the treatment of lung cancer and potentially other radiation-resistant cancers. Citation Format: Tianyuan Wang, Hashini Wanniarachchi, Lorena Arango, Li Zhang, Li Liu. Evaluating therapeutic strategies against lung cancer using multispectral optoacoustic tomography [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5979.
Abstract 5800: Germline pathogenic variant of cancer predisposition genes in pancreatic cancer patients
Authors: Yena Kim, Min Kyeong Kim, Kum Hei Ryu, Hyoeun Shim, Ji Sun Han, Jung Won Chun, Yun-Hee Kim, Ju Sun Song, Young-gon Kim, Sang Myung Woo, Sun-Young Kong
Journal: Cancer Research (2022)

Abstract Purpose: Genetic attribution for pancreatic cancer has been reported as 2-10%. However, the incidence of genetic predisposition and germline pathogenic variants (PVs) in Korean pancreatic cancer patients has not been well investigated. Therefore we studied to identify the clinical characteristics of the causative gene mutations and incidence of PV for future treatment strategies in pancreatic cancer. Methods: Total of 283 (145 male and 138 female) patients were enrolled in National Cancer Center in Korea (IRB no. NCC2019-0034, NCC2021-0338) and their median age was 67 years (range: 33-90). Resectable (25.1%), borderline resectable or locally advanced (25.5%), and metastatic (46.3%) stages were included. Germline hereditary cancer panel tests with 28 genes and BRCA1/2 gene were done in 97.2% (n=275) and 2.8% (n=8) of patients, respectively. Results: PVs were detected in 17 patients (median age 64, range 49-80) in ATM (n=5, 29.4%), BRCA1 (n=3, 17.6%), BRCA2 (n=2, 11.8%), RAD51D (n=2, 11.8%), TP53 (n=1, 5.9%), PALB2 (n=1, 5.9%), PMS2 (n=1, 5.9%), RAD50 (n=1, 5.9%), and SPINK1 (n=1, 5.9%). Eight patients (4 ATM PVs, 2 BRCA1 1 BRCA2, 1 PALB2 PV) presented various type of cancers in their families and three patients with ATM PVs showed pancreatic cancer in their first degree relatives. Nine patients without family cancer history represented median age as 66 (49-80) which was not significantly different of those with family history as 63 (51-75). Conclusions: This study showed 6.0% of incidence of germline PVs in Korean pancreatic cancer patients. Though we still don’t have guidelines for germline predisposition gene test in pancreatic cancer patients in Korea, this result showed that the incidence of PVs were comparable with that of the country which have recommendation to do genetic tests for all pancreatic cancer patients. To expand our knowledge for the incidence and involving genes of cancer predisposition for Korean pancreatic cancer patients, further analysis in larger number of patients is needed. (This study was supported by National cancer center, Korea, Grant no. 2110181).Keywords: Germ-line Mutation; Pancreatic Neoplasms; Incidence Citation Format: Yena Kim, Min Kyeong Kim, Kum Hei Ryu, Hyoeun Shim, Ji Sun Han, Jung Won Chun, Yun-Hee Kim, Ju Sun Song, Young-gon Kim, Sang Myung Woo, Sun-Young Kong. Germline pathogenic variant of cancer predisposition genes in pancreatic cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5800.
Abstract 2907: 1C3, a Novel non-blocking anti-human TNFR2 antibody generated from RenMice, exhibits promising anti-tumor activity and safety in syngeneic tumor models in humanized TNFR2 mice
Authors: Yongfei Yang, Shuzhen Cao, Jing Zhang, Zhe Shao, Xueyuan Jiang, Qingya Duan, Maopeng Tian, Sen Mei, Luke (Zhaoxue) Yu
Journal: Cancer Research (2022)

Abstract Regulatory T Cells (Treg) inhibit effector T cell (Teff) activity in the tumor microenvironment (TME). Therefore, depletion of regulatory T cells (Treg cells) is a promising therapeutic strategy for tumor immunotherapy. Tumor necrosis factor receptor-2 (TNFR2) is highly expressed on Treg cells and is a potential target for anti-tumor therapy. A TNFR2 non-blocking antibody (1C3) was generated from humanized IgG mice (RenMice), which is an effective platform for human antibody generation. 1C3 was selected from a large panel of antibody candidates through an unbiased, high-throughput in vivo efficacy screen in syngeneic tumor mouse models in humanized TNFR2 mice. Compared with other TNFR2 antagonistic antibodies, 1C3 effectively promoted the proliferation of CD8+ cytotoxic T cells in vitro, a population that is inhibited by Treg cells. To evaluate 1C3 efficacy and safety in vivo, syngeneic mouse tumor models were established. 1C3 monotherapy significantly inhibited tumor growth in a dose-dependent manner in syngeneic tumor mouse models in TNFR2 humanized mice. In combination with anti-human PD-1 or PD-L1 antibody, 1C3 also greatly increased antitumor activity compared to the monotherapy of each therapeutic agent. Mechanistically, 1C3 treatment significantly increased the ratio of Teff/Treg in the TME. In addition, 1C3 was well tolerated in TNFR2 humanized mice, and no side effects were observed even when the dose was increased to 100 mg/kg. Taken together, our data demonstrates that 1C3 is a novel anti-TNFR2 antibody for anti-tumor therapy and provides a great potential for the next generation of immunotherapy. Citation Format: Yongfei Yang, Shuzhen Cao, Jing Zhang, Zhe Shao, Xueyuan Jiang, Qingya Duan, Maopeng Tian, Sen Mei, Luke (Zhaoxue) Yu. 1C3, a Novel non-blocking anti-human TNFR2 antibody generated from RenMice, exhibits promising anti-tumor activity and safety in syngeneic tumor models in humanized TNFR2 mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2907.
Fine-Tuning Cardiac Insulin-Like Growth Factor 1 Receptor Signaling to Promote Health and Longevity
Authors: Mahmoud Abdellatif, Viktoria Trummer-Herbst, Alexander Martin Heberle, Alina Humnig, Tobias Pendl, Sylvère Durand, Giulia Cerrato, Sebastian J. Hofer, Moydul Islam, Julia Voglhuber, José Miguel Ramos Pittol, Oliver Kepp, Gerald Hoefler, Albrecht Schmidt, Peter P. Rainer, Daniel Scherr, Dirk von Lewinski, Egbert Bisping, Julie R. McMullen, Abhinav Diwan, Tobias Eisenberg, Frank Madeo, Kathrin Thedieck, Guido Kroemer, Simon Sedej
Journal: Circulation (2022)

Background: The insulin-like growth factor 1 (IGF1) pathway is a key regulator of cellular metabolism and aging. Although its inhibition promotes longevity across species, the effect of attenuated IGF1 signaling on cardiac aging remains controversial. Methods: We performed a lifelong study to assess cardiac health and lifespan in 2 cardiomyocyte-specific transgenic mouse models with enhanced versus reduced IGF1 receptor (IGF1R) signaling. Male mice with human IGF1R overexpression or dominant negative phosphoinositide 3-kinase mutation were examined at different life stages by echocardiography, invasive hemodynamics, and treadmill coupled to indirect calorimetry. In vitro assays included cardiac histology, mitochondrial respiration, ATP synthesis, autophagic flux, and targeted metabolome profiling, and immunoblots of key IGF1R downstream targets in mouse and human explanted failing and nonfailing hearts, as well. Results: Young mice with increased IGF1R signaling exhibited superior cardiac function that progressively declined with aging in an accelerated fashion compared with wild-type animals, resulting in heart failure and a reduced lifespan. In contrast, mice with low cardiac IGF1R signaling exhibited inferior cardiac function early in life, but superior cardiac performance during aging, and increased maximum lifespan, as well. Mechanistically, the late-life detrimental effects of IGF1R activation correlated with suppressed autophagic flux and impaired oxidative phosphorylation in the heart. Low IGF1R activity consistently improved myocardial bioenergetics and function of the aging heart in an autophagy-dependent manner. In humans, failing hearts, but not those with compensated hypertrophy, displayed exaggerated IGF1R expression and signaling activity. Conclusions: Our findings indicate that the relationship between IGF1R signaling and cardiac health is not linear, but rather biphasic. Hence, pharmacological inhibitors of the IGF1 pathway, albeit unsuitable for young individuals, might be worth considering in older adults.